Neuronal Protein Tyrosine Phosphatases in Metabolism

肥胖症和合并症如II型糖尿病的日益普遍， 世界范围内严重的健康问题。了解细胞信号通路的基础 这些病理状态对于帮助开发潜在的治疗性治疗是至关重要的。 了以下条件瘦素是一种由脂肪分泌的激素，作用于中枢神经元， 神经系统（CNS）调节食物摄入和能量消耗。瘦素启动一个 细胞内信号级联反应，这反过来又导致离子通道活性和基因的变化 最终保持能量平衡的表达。瘦素信号通路紧密地 由酪氨酸磷酸化控制，两种蛋白酪氨酸磷酸酶（PTPs） 最近被认为与大脑中瘦素信号通路的调节有关：PTP 1B和 SHP2.这些PTP在调节能量平衡中显然具有重要的体内作用，但是 精确的神经元作用位点和细胞水平上PTP 1B/SHP 2作用机制 是未知的。下丘脑的POMC和AgRP神经元是两者的重要部位 能量平衡和葡萄糖稳态调节。我们假设PTP 1B和SHP 2 具有重要的代谢作用，特别是在这些神经元通过瘦素依赖或- 独立的影响。我们的具体目标是解决PTP 1B或SHP 2缺失的影响， 特别是在POMC-或AgRP-表达神经元的小鼠体重，肥胖，瘦素 敏感性和葡萄糖耐量。此外，这些研究将探讨PTP 1B或 下丘脑神经元中SHP 2的缺失影响这些神经元的电生理特性。 神经元这种遗传、生物化学和电生理技术的结合将 提供有关PTP作用于下丘脑的细胞机制的基本信息 与能量平衡有关的神经元。

The increasing prevalence of obesity and co-morbidities such as type II diabetes poses a significant health problem worldwide. Understanding the cellular signaling pathways underlying these pathological states is critical to assist in developing potential therapeutic treatment of these conditions. Leptin is a hormone secreted by fat, which acts on neurons in the central nervous system (CNS) to regulate food intake and energy expenditure. Leptin initiates an intracellular signaling cascade which in turn leads to changes in ion channel activity and gene expression that ultimately keep energy balance in check. The leptin signaling pathway is tightly controlled by tyrosine phosphorylation, and two protein tyrosine phosphatases (PTPs) have recently been implicated in regulation of the leptin signaling pathway in the brain: PTP1B and SHP2. These PTPs clearly have important in vivo roles in regulating energy balance, but the precise neuronal site(s) of action and the mechanism of PTP1B/SHP2 action at a cellular level are unknown. POMC and AgRP neurons in the hypothalamus are an important site of both energy balance and glucose homeostasis regulation. We hypothesize that PTP1B and SHP2 have important metabolic roles specifically in these neurons via either leptin-dependent or - independent effects. Our specific aims will address the effects of PTP1B or SHP2 deletion specifically in POMC- or AgRP-expressing neurons of mice on body weight, adiposity, leptin sensitivity, and glucose tolerance. Furthermore, these studies will address how PTP1B or SHP2 deletion in hypothalamic neurons affects the electrophysiological properties of these neurons. This combination of genetic, biochemical, and electrophysiological techniques will provide essential information about the cellular mechanism of PTP action in hypothalamic neurons as relates to energy balance.